Process for preparing 5-(4-fluorophenyl)-1-[2r,4r)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl) ethyl]-2-isopropyl-4-phenyl-1h-pyrrole-3-carboxylic acid phenylamide

ABSTRACT

A method for preparing 5-(4-fluorophenyl)-1[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide (I), a key intermediate in the synthesis of atorvastatin calcium, is described.

This application claims benefits of U.S. Provisional Application No.60/462,613, filed on Apr. 14, 2003.

FIELD OF THE INVENTION

A method for preparing5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide, a key intermediate in the synthesis of atorvastatincalcium, is described.

BACKGROUND OF THE INVENTION

5-(4-Fluorophenyl)-1-[2-((2R,4R)-4hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide (I) is a key intermediate in the synthesis ofatorvastatin calcium (Lipitor®), known also by the chemical name[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1) trihydrate. Atorvastatin calcium inhibits3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) andthus is useful as a hypolipidemic and/or hypocholesterolemic agent.

A number of patents have issued disclosing approaches to the preparationof atorvastatin calcium, as well as various analogues, via intermediatessuch as compound (I). These patents include: U.S. Pat. Nos. 4,681,893;5,273,995; 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837;5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792;5,342,952; 5,298,627; 5,446,054; 5,470,981; 5,489,690; 5,489,691;5,510,488; 5,998,633; and 6,087,511; 5,969,156; 6,121,461; 5,273,995;6,476,235; U.S. Application Ser. No. 60/401,707 (filed Aug. 6, 2002).

Existing approaches to the preparation of key intermediate (I) presentedsome shortcomings. For example, one approach relied on the use of acostly chiral raw material ((R)-4-cyano-3-hydroxy-butyric acid ethylester), and a low temperature diastereoselective borane reduction.

Scheme 1 summarizes an alternative approach disclosed in U.S. Pat. No.6,476,235. Hydrogenation of β,δ diketoester 2 in the presence of achiral ruthenium catalyst under acidic conditions proceeded to give diol3 in low yields and 1:1 syn:anti diastereoselectivity with respect tothe C-3 and C-5 chiral centers.

As a preliminary matter, asymmetric hydrogenations of ketones asdescribed above for the transformation of 2 to 3 are known. However, thecomplexity of the reaction increases in the case of 1,3,5-tricarbonylsystems such as 2, and poor yields and poor stereoselectivities oftenresult. In fact, investigations by Saburi (Tetrahedron, 1997, 1993; 49)and Carpentier (Eur. J. Org. Chem. 1999; 3421) have independentlydemonstrated low to moderate diastereo- and/or enantio-selectivities fordiketoester asymmetric hydrogenations. Furthermore, the fact that theprocesses disclosed in the literature require high pressurehydrogenation and extended reaction times makes the procedures generallyimpractical and not amenable to large-scale manufacturing processeswhere safety, efficiency, and cost are critical considerations.

Referring again to Scheme 1, a number of additional transformations arenecessary to reset the stereochemistry of the C-3 center in diol 3 toprovide key intermediate (I). These steps include: (a) intramolecularcyclization of 3 to provide lactone 4; (b) elimination of water fromlactone 4 using acid to provide α,β unsaturated lactone 5; (c) facialselective Michael addition of allyl or benzyl alcohol to α,β unsaturatedlactone 5 to provide saturated lactone 6; and removal of the allyl orbenzyl moiety in lactone 6 via hydrogenolysis to provide keyintermediate (I).

As a result, a need remains for an approach to the preparation of keyintermediate (1) that is efficient, inexpensive, proceeds in a minimumof transformations, and occurs in good yield and high levels ofdiastereoselectivity.

SUMMARY OF THE INVENTION

These and other needs are met by the present invention which is directedto a process for the preparation of a compound of formula (I)

comprising:

-   -   (a) contacting in a solvent optionally in the presence of a        Lewis acid a compound of formula (II) with    -   wherein M is SiCl₃, SiMe₃, B(OH)₂, CuLi, MgBr, ZnBr, InBr, SnR₃        wherein R₃ is (C₁-C₆)alkyl, to give a compound of formula (III):    -   (b) conversion of the compound of formula (III) to an acryloyl        ester of formula (IV) in the presence of base using    -   wherein X is Cl, Br, I, or    -   and R is H, (C₁-C₆)alkyl, or phenyl, or an acryloyl activated        ester equivalent;    -   (c) contacting in a solvent the acryloyl ester (IV) with a        catalyst to afford 5,6 dihydro pyran-2-one V;    -   (d) converting the compound of formula (V) to a compound of        formula (VI) via facial selective 1,4 addition of allyl or        benzyl alcohol;    -   (e) removal of the allyl or benzyl moiety in the compound of        formula (VI) via hydrogenolysis to give a compound of formula I.

What is also disclosed is a process for the preparation of a compound offormula (I)

comprising:

-   -   (a) contacting in a solvent optionally in the presence of a        Lewis acid a compound of formula (II) with    -   wherein M is SiCl₃, SiMe₃, B(OH)₂, CuLi, MgBr, ZnBr, InBr, SnR₃        wherein R₃ is (C₁-C₆)alkyl, to give a compound of formula (VII):    -   (b) conversion of the compound of formula (VII) with concomitant        stereochemical inversion of the homoallylic alcohol center to an        acryloyl ester of formula (IV) via Mitsunobu reaction in the        presence of acrylic acid or an acrylic acid analogue    -   wherein R is H, (C₁-C₆)alkyl, or phenyl, in the presence of        base;    -   (c) contacting in a solvent the acryloyl ester (IV) with a        catalyst to afford 5,6 dihydro pyran-2-one V;    -   (d) converting the compound of formula (V) to a compound of        formula (VI) via facial selective 1,4 addition of allyl or        benzyl alcohol;    -   (e) removal of the allyl or benzyl moiety in the compound of        formula (VI) via hydrogenolysis to give a compound of formula I.

What is further disclosed is a process for the preparation of a compoundof formula (I)

comprising:

-   -   (a) contacting in a solvent optionally in the presence of a        Lewis acid a compound of formula (II) with    -   wherein M is SiCl₃, SiMe₃, B(OH)₂, CuLi, MgBr, ZnBr, InBr, SnR₃        wherein R₃ is (C₁-C₆)alkyl, to give a compound of formula        (VIII):    -   (b) isolating the desired enatiomer (III) from the enantiomeric        mixture;    -   (c) conversion of the compound of formula (III) to an acryloyl        ester of formula (IV) in the presence of base using    -   wherein X is Cl, Br, I, or    -   and R is H, (C₁-C₆)alkyl, or phenyl, or an acryloyl activated        ester equivalent;    -   (d) contacting in a solvent the acryloyl ester (IV) with a        catalyst to afford 5,6 dihydro pyran-2-one V;    -   (e) converting the compound of formula (V) to a compound of        formula (VI) via facial selective 1,4 addition of allyl or        benzyl alcohol;    -   (f) removal of the allyl or benzyl moiety in the compound of        formula (VI) via hydrogenolysis to give a compound of formula I.

What is also provided is a process for the preparation of a compound offormula III

comprising:

-   -   (a) contacting a compound of formula (II) with an allenylboronic        ester to give a compound of formula (XI):    -   (b) hydrogenation of the compound of formula (XI) to provide a        compound of formula III

What is also provided is a process for the preparation of a compound offormula VII

comprising:

-   -   (a) contacting contacting (II) with an allenylboronic ester to        give a compound of formula (XII):    -   (b) hydrogenation of the compound of formula (XII) to provide        the compound of formula (VII)

What is also provided is a process for the preparation of a compound offormula VIII

comprising:

-   -   (a) contacting a compound of formula (II) with allenylboronic        acid or an allenylboronic ester to give a compound of formula        (XIII):    -   (b) hydrogenation of the compound of formula (X) to provide VII

What is also provided is a compound of formula III.

What is also provided is a compound of formula VIII.

What is also provided is a compound of formula VII.

What is also provided is a compound of formula IX.

What is also provided is a compound of formula IV.

What is also provided is a compound of formula X.

What is also provided is a compound of formula XI.

What is also provided is a compound of formula XII.

What is also provided is a compound of formula XIII.

As disclosed herein, we surprisingly and unexpectedly found that 5,6dihydro pyran-2-one (V) can be obtained conveniently from acryloyl ester(IV) via a mild and efficient one-step ring-closing metathesis reactionin the presence of a homogeneous catalyst. The reaction proceeds in goodyields at temperatures below approximately 60° C. and atmosphericpressure. The invention process is thus safer and more efficient inlarge scale than earlier approaches, because it avoids the need forspecialized high-pressure equipment. In addition, a minimum number oftransformations are necessary to incorporate the C-3 hydroxy group, andthe overall number of steps needed to convert the compound of formula(II) to key intermediate (I) is minimized. Moreover, the inventionprocess avoids the use of a costly, chiral raw material((R)-4-cyano-3-hydroxy-butyric acid ethyl ester), and a low temperaturediastereoselective borane reduction, as was necessary in earlierapproaches to the preparation of key intermediate (I).

DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS

(C₁-C₆)alkyl means both straight and branched groups; but reference toan individual radical such as “propyl” embraces only the straight chainradical, a branched chain isomer such as “isopropyl” being specificallyreferred to. Thus, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl.

The term “approximate” as used herein in reference to a quality,condition, or amount, means the value specified in relation to thequality, condition, or amount is nearly exact, or nearly or more or lessas specified.

If ranges defined by two endpoints are provided for a particular valuedisclosed herein (relating, for instance, to reaction temperature, time,concentration, or stoichiometry), that range is intended to cover theendpoints and all real values, both fractions and integers between theendpoints.

Invention Process

As a preliminary matter, the compounds prepared by the invention processdisclosed herein may have one or more chiral centers and may exist inand be used or isolated in optically active and racemic forms. Thus, itis to be understood that the processes of the present invention can giverise to any racemic or optically-active forms, or mixtures thereof, asdescribed herein. It is to be further understood the products of theinvention process can be isolated as racemic, enantiomeric, ordiastereomeric forms, or mixtures thereof. Purification andcharacterization procedures for such products are known to those ofordinary skill in the art, and include recrystallization techniques, aswell as chiral chromatographic separation procedures as well as othermethods.

The invention process disclosed herein is summarized in Scheme 2.Although it depicts the synthesis of the desired chiral series, thesequence of reactions disclosed in Scheme 2 can be modified as needed(i.e., by use of chiral versus non-chiral auxiliaries, Lewis acids, orligands, depending on the reaction type) to provide both chiral andnon-chiral products.

The invention process commences with step (a)or step (a-1)/(a-2). Instep (a), allylation of aldehyde (II) provides homoallylic alcohol III.In step (a-1)l(a-2), addition of an allenylboronic ester to aldehyde(II) provides homopropargylic alcohol XI. Hydrogenation ofhomopropargylic alcohol (XI) in step (a-2) provides homoallylic alcoholIII.

In step (b), the hydroxyl group in compound (III) is allowed to reactwith acryloyl chloride to provide acryloyl ester IV. In step (c), aring-closing metathesis reaction provides key intermediate V. In step(d), the C-3 hydroxyl group, protected as the corresponding benzyl orallylic ether, is appended stereoselectively to the compound V. Removalof the protecting group and hydrogenolysis provides compound I.

The synthetic sequence disclosed in Scheme 2 is described in greaterdetail in the following sections.

Step (a)

In step (a) of the invention process, the aldehyde (II) undergoesallylation using

wherein M is SiCl₃, SiMe₃, B(OH)₂, CuLi, MgBr, ZnBr, InBr, SnR₃ whereinR₃ is (C₁-C₆)alkyl,to provide homoallylic alcohol III. Methods forperforming the allylation of aldehydes are well known and are widelyavailable to the skilled artisan and typically rely on the use of aGrignard reagent (e.g., allyl magnesium bromide) or a Grignard reagentequivalent, such as an allyl zinc, allyl borane (such as allyldihydroxyborane), an allylboronic ester, allyl cuprate, allyl tin (suchas allyl tri-n-butylstannane), allyl silane (such as allyltrichlorosilane or allyl triemthylsilane), or allyl indium reagent.Methods for preparing and using these reagents are well known to theskilled artisan based on reports in the chemical literature. Many arealso commercially available.

A Lewis acid optionally may be used to mediate asymmetric inductionand/or mediate the allylation reaction. The use of Lewis acids is wellknown in organic synthesis. See Hisashi Yamamoto, Lewis acids in OrganicSynthesis (2002). In a non-chiral embodiment of the invention process, anon-chiral Lewis acid may be used to catalyze the allylation process, asdepicted in Scheme 3, to provide homoallylic alcohol (VIII) as a racemicmixture. In this series, the desired enantiomer (III) can be isolatedusing procedures available to the skilled artisan, for instance, bychromatographic separation using a chiral stationary phase or resolutionof the racemic form by established recrystallization techniques.

In another embodiment of step (a) of Scheme 2, a chiral Lewis acid canbe used to control the enantioselectivity, as well as to mediate theprocess. In one embodiment of the invention process, a Lewis acidgenerated in situ, derived from boron tribromide and(S,S)-1,2-diamino-1,2-diphenylethane bis-toluenesulfonamide, wasemployed to provide a 94.4% enantiomeric excess of the desired S isomeras shown in Scheme 2.

In yet another embodiment of step (a) of Scheme 2, as depicted in Scheme4, the opposite enantiomer (VII) also can be synthesized by choosing anappropriate chiral Lewis acid. In this reaction variant, compound (VII)is readily converted to the preferred enantiomer (III) under conditionsavailable to the skilled artisan. For instance, Mitsunobu-type reactionof (VII) in the presence of triphenyl phosphine, tributyl phosphine orthe like, diethylazodicarboxylate or an equivalent reagent such asdi-ispopropylazodicarboxylate or 1,1′(azodicarbonyl)dipiperidine, and acarboxylic acid such as benzoic, formic, or acetic acid, will provideester IIIa. Ester IIIa readily may be converted to homoallylic alcohol(III) under reduction or hydrolysis conditions available to the skilledartisan. Alternatively, acrylic acid can be used as the acid componentof the Mitsunobu-reagent system, to provide homoallylic ester (III) inone pot.

An alternative approach to the conversion of compound (VII) to compound(III) is also depicted in Scheme 4 and requires conversion of thealcohol moiety in compound (VII) to a leaving group such as a mesylateor tosylate, for instance, by mesylation or tosylation or the like,followed by nucelophilic displacement with an appropriate oxygennucleophile such as acetate to provide the ester. Reduction orhydrolysis of the ester provides compound III. Methods are readilyavailable to the skilled artisan for performing this sequence oftransformations.

It is worth noting that a Lewis acid is not a necessary reactioncomponent in some cases, as when allyl trichlorosilane is employed inthe presence of an amino alcohol or diamine. See Kinnaird, et. al., J.Am. Chem. Soc. 2002, 124, 7920. It is also worth noting that thereaction proceeds in the presence of a Lewis Base when allyltrichlorosilane is used. See Denmark, et. al., J. Am. Chem. Soc. 2001,123, 9488.

In one embodiment of step (a) of the invention process, thestoichiometry of the allylation reaction components is typicallyapproximately:

1.0 equivalent of aldehyde;

1.05-1.5 equivalents of Lewis acid; and

1.05-1.5 equivalents of allyl Grignard reagent or allyl Grignardequivalent reagent.

In another embodiment of the invention process, the stochimetry of theallylation reaction is typically approximately:

1.0 equivalent of aldehyde;

1.05-1.3 equivalents of Lewis acid; and

1.05-1.3 equivalents of allyl Grignard reagent or allyl Grignardequivalent reagent.

In still another embodiment of the invention process, the stochimetry ofthe allylation reaction is typically approximately:

1.0 equivalent of aldehyde;

1.05-1.2 equivalents of Lewis acid; and

1.05-1.2 equivalents of allyl Grignard reagent or allyl Grignardequivalent reagent.

In one embodiment of the invention process, the concentration of thealdehyde in dichloromethane is typically approximately 0.05 to 0.125 mM.

In another embodiment of the invention process, the concentration of thealdehyde in dichloromethane is typically approximately 0.075 to 0.10 mM.

In still another embodiment of the invention process, the concentrationof the aldehyde in dichloromethane is typically approximately 0.08 to0.09 mM.

The temperature of the allylation reaction typically is in the range ofapproximately −78° C. to approximately room temperature, or 25° C.

The time required for the allylation reaction typically is in the rangeof approximately 12 to approximately 24 hours, or until the conventionalanalytical techniques such as TLC or HPLC indicate that the reaction hasachieved completion.

In general, the time and temperature parameters of the allylationreaction will vary somewhat depending on reaction concentration andstoichiometry. The skilled artisan can readily adjust the reactionparameters as needed to optimize reaction yields on a run-by-run basis.

In a typical procedure employing a chiral Lewis acid generated in situ,(S,S)-1,2-diamino-1,2-diphenylethane bis-toluenesulfonamide is dissolvedin a polar non-protic solvent. Polar non-protic solvents useful in thefirst step of the invention process include, for example,dichloromethane, chloroform, 1,1,1 trichloroethane, 1,1,2trichloroethane and the like. Typically, dichloromethane is used. Themixture of the chrial auxiliary in solvent is then cooled to 0° C. andBBr₃ is added dropwise at a rate sufficient to maintain the reactiontemeperature at 0° C. The resulting mixture is stirred at 0° C. for 10minutes and then is allowed to warm to room temperature, is stirred foran additional 40 minutes, and is then concentrated in vacuo. The residueis taken up in a solvent such as dichloromethane and concentrated invacuo again to remove excess boron tribromide. The residue is thendissolved in dichloromethane and the resulting mixture is cooled to 0°C. To this cooled reaction mixture is added an allyl metal reagent suchas tributylstannane, after which the resulting mixture is warmed toambient temperature and stirred for approximately 1 to approximately 4hours. The mixture is cooled to −78° C. and the aldehyde (II) dissolvedin dichloromethane is added dropwise. The mixture is then stirred for anadditional 12 to 24 hours. Conventional workup and purification affordsthe desired product.

Step (a) Alternative: Steps (a-1)and (a-2)

An alternative to step(a) is depicted in step (a-1) and step (a-2) andinvolves the addition of an allenylboronic ester to aldehyde (II) toprovide the homopropargylic alcohol XI, followed by hydrogenation.

Step (a-1)

The reaction of allenylboronic esters with aldehydes, and more notably,the use of chiral allenylboronic esters in enantoselective synthesis, iswell known to the skilled artisan. See R. Haruta, M. Ishiguro, N. Ikeda,and H. Yamamoto. J. Am. Chem. Soc. 1982, 104, 7667; N. Ikeda and H.Yamamoto. J. Am. Chem. Soc. 1986, 108, 483;E. J. Corey, C.-M. Yu, andD.-H. Lee. J. Am. Chem. Soc. 1990, 112, 878.

In a non-chiral context, treatment of aldehyde (II) with allenylboronicacid, prepared as described in N. Ikeda and H. Yamamoto. J. Am. Chem.Soc. 1986, 108, will give rise homopropargylic alcohol XIII, as depictedin Scheme 5.

In a chiral context, depending on the chiral auxiliary employed, eitherhomopropargylic acid (XI) or (XII) may be prepared, as shown in Scheme6. For example, as described in R. Haruta, M. Ishiguro, N. Ikeda, and H.Yamamoto. J. Am. Chem. Soc. 1982, 104, 7667 or N. Ikeda and H. Yamamoto.J. Am. Chem. Soc. 1986, 108, 483, the addition of a chiralallenylboronic ester generated from allenylboronic acid using(+)-dialkyl tartrate, such as diethyl, di-isopropyl, dicyclopentyl,dimenthyl, dicyclododecyl, or di-2,4-dimethyl-3-pentyl tartrate, willgive rise to homopropargylic acid XI. The use of a (−)-dialkyl tartratewill provide homopropargylic acid XII. Other variants of the approachare known to the skilled artisan and include, for example, the proceduredescribed in E. J. Corey, C.-M. Yu, and D.-H. Lee. J. Am. Chem. Soc.1990, 112, 878.

In a typical procedure, allenylboronic acid can be combined with(+)-diethyl tartrate in tetrahydrofuran as described in N. Ikeda and H.Yamamoto. J. Am. Chem. Soc. 1986, 108. The tetrahydrofuran can beremoved in vacuo, leaving the allenylboronic ester, which can be usedwithout further purification. Aldehyde (II) can be added to a solutionof the allenylboronic ester in toluene or the like at from approximately−80 to approximately −10° C. Conventional work-up (extraction intodiethyl ether, drying over magnesium sulfate, and concentration invacuo) and purification (silica gel column chromatography) will giverise to homopropargylic alcohol XI. The same procedure, except employing(−)-diethyl tartrate, will give rise to homopropargylic alcohol XII.

Step (a-2)

Hydrogenation of homopropargylic alcohol (XI) will provide homoallylicalcohol III. Conditions for effecting the hydrogenation are well knownto the skilled artisan and may be carried out under heterogeneousconditions or homogeneous conditions. The heterogeneous catalyst knownas Lindlar's catalyst, which is a lead-modified palladium-CaCO₃catalyst, is generally employed for this transformation (See H. Lindlarand R. Dubuis. Org. Synth. 1973, V, 880).

Step (b)

In step (b) of the invention process, homoallylic alcohol (III) isconverted to the acryloyl ester (IV) upon reaction with

wherein X is Cl, Br, I, or

and R is H, (C₁-C₆)alkyl, or phenyl, or upon reaction with an acryloylactivated ester equivalent, in the presence of base. “Acryloyl activatedester equivalent” means an acryloyl mixed anhydride wherein X is asterically hindered moiety such as

It also means an acryolyl mixed anydride generated from a chloroformate,or from carbonyl di-imidazole. The reaction of an alcohol with an acidchloride, anhydride, or mixed anhydride is well known in the art (See,for example, Junzo Otera, Esterification: Methods, Reactions, andApplications, Wiley-VCH, Weinheim, 2003). In general, the reactionrequires the use of an amine base such as triethylamine,di-isopropylethylamine, DBU, or DBN, or the like, in the presence of acatalytic amount of 4-(dimethylamino)pyridine (MAP). The transformationproceeds smoothly without protection of the amide nitrogen. Alternativeprocedures may also be used, such as relying on the use of carbodiimidecoupling reagents.

In one embodiment of the invention process, the stoichiometry of thereaction components in the esterification reaction is typicallyapproximately:

1.0 equivalent of homoallylic alcohol;

1.05-1.5 equivalents of acryolyl chloride;

1.05-1.5 equivalents of amine base; and

0.1 to 0.5 equivalent DMAP.

In another embodiment of the invention process, the stoichiometry of thereaction is typically approximately:

1.0 equivalent of homoallylic alcohol;

1.1-1.4 equivalents of acryolyl chloride;

1.1-1.4 equivalents of amine base; and

0.15 to 0.4 equivalent DMAP.

In still another embodiment of the invention process, the stoichiometryof the reaction is typically approximately:

1.0 equivalent of homoallylic alcohol;

1.15-1.3 equivalents of acryolyl chloride;

1.15-1.3 equivalents of amine base; and

0.2 to 0.3 equivalent DMAP.

In one embodiment of the invention process, the concentration of theacrylate ester in dichloromethane is typically approximately 0.01 to0.05 mM.

In another embodiment of the invention process, the concentration of theacrylate ester in dichloromethane is typically approximately 0.015 to0.045 mM.

In still another embodiment of the invention process, the concentrationof the aldehyde in dichloromethane is typically approximately 0.02 to0.04 mM.

The temperature of the esterification reaction typically is in the rangeof approximately room temperature, or approximately −5° C., toapproximately 20° C.

The time required for the reaction typically is in the range ofapproximately 4 to approximately 24 hours, or until the conventionalanalytical techniques such as TLC or HPLC indicate that the reaction hasachieved completion.

In general, the time and temperature parameters of the reaction willvary somewhat depending on reaction concentration and stoichiometry. Theskilled artisan can readily adjust the reaction parameters as needed tooptimize reaction yields on a run-by-run basis.

In a typical procedure,5-(4-Fluoro-phenyl)-1-(3-hydroxy-hex-5-enyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide (III) is dissolved in a polar non protic solvent suchas dichloromethane. The reaction is cooled to −5° C. and an amine basesuch as triethylamine is added, along with a catalytic amount of4-(dimethyl amino)pyridine (DMAP). To this cooled reaction mixture isslowly added acryloyl chloride dissolved in dichloromethane. Additionaltriethylamine and/or DMAP may be added as needed to drive the reactionto completion. The reaction mixture is quenched, worked up, and purifiedunder conventional conditions to provide IV.

Step (c)

In step (c) of the invention process, acryloyl ester (IV) undergoesring-closing metathesis in the presence of a homogeneous organometalliccatalyst to provide 5,6 dihydro pyran-2-one IV. A number of metalcatalysts are available for the purpose of performing ring-closingmetathesis reactions, including, for instance, commercially availablebis(tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride A(“Grubbs' Catalyst) in the presence or absence of Ti(O-iPr)₄ (G. C. Fuand R. H. Grubbs, J. Am. Chem. Soc., 1992, 114, 5426; See also A. K.Ghosh and H. Lei, J. Org. Chem., 2000, 65, 4779 and references citedtherein; Grubbs, R. H. and Chang, S., Tetrahedron Lett., 1998, 54, 4413;Cossy, J., Pradaux, F. and BouzBouz, S., Org. Lett., 2001, 3, 2233;Held, C., Frohlich, R. and Metz, P., Ang. Chem. Int. Ed. Eng., 2001, 40,1058; Reddy, M. V., Rearick, J. P., Hoch, N. and Ramachandran, P. V.,Org. Lett., 2001, 3, 19; P. V. Ramachandran, M. V. Reddy, and H. C.Brown, J. Indian. Chem. Soc., 1999, 76, 739; Greer, P. B. and Donaldson,W. A., Tetrahedron Lett., 2000, 41, 3801; Ghosh, A. and Wang, Y.Tetrahedron Lett., 2000, 41, 2319; Ghosh, A. and Bilcer, G., TetrahedronLett., 2000, 41, 1003; Ramachandran, P. V., Reddy, M. V., and Brown, H.C., Ghosh, A. and Wang, Y. Tetrahedron Lett., 2000, 41, 583; Ghosh, A.,and Liu, C., Chem. Commun., 1999, 1743; Ghosh, A. K., Capiello, J., andShin, D. Ghosh, A. and Wang, Y. Tetrahedron Lett., 1998, 39, 4651;Reddy, M. V., Yucel, A., Ramachandran, P. V., J. Org. Chem., 2001, 66,2512).

An alternative catalyst for use in the metathesis reaction of theinvention process is B.

See,.e.g., Schrock, R. R., Murdzek, J. S., Bazan, G. C., Robbins, J.,DiMare, M., and O'Regan, M. B., J. Am. Chem. Soc. 1990, 112, 3875;Bazan, C., Khosravi, E., Schrock R. R., Feast, W. J., Gibson, V. C.,O'Regan, M. B., Thomas, J. K., Davis, W. M., J. Am. Chem. Soc., 1990,112, 8378; Bazan, C., Oskam, J. H., Cho, H. N., Park, L. Y., Schrock, R.R., J. Am. Chem. Soc., 1991, 113, 6899.

An additional alternative reaction approach is to generate the catalystin situ, as provided in Morgan, J. P. and Grubbs, R. H., Org. Lett.,2000, 2, 3153; Huang, J., Stevens, E. D., Nolan, S. P., Petersen, J. L.,J. Am. Chem. Soc., 1999, 121, 2674; Furstner, A., Thiel, O., Ackerman,L., Schanz, H.-J. and Nolan, S. P. J. Org. Chem., 2000, 65, 2204). Suchcatalysts include, for example,

the like.

In one embodiment of the invention process, the stoichiometry of thereaction components is typically approximately:

1.0 equivalent of acrylate ester; and

0.025-0.075 equivalents of catalyst.

In another embodiment of the invention process, the stoichiometry of thereaction is typically approximately:

1.0 equivalent of acrylate ester; and

0.04-0.06 equivalents of catalyst.

In still another embodiment of the invention process, the stoichiometryof the reaction is typically approximately:

1.0 equivalent of acrylate ester; and

0.045-0.055 equivalents of catalyst.

In one embodiment of the invention process, the concentration of theacrylate ester in dichloromethane is typically approximately 0.05 to0.125 mM.

In another embodiment of the invention process, the concentration of theacrylate ester in dichloromethane is typically approximately 0.08 to0.11 mM.

In still another embodiment of the invention process, the concentrationof the acrylate ester in dichloromethane is typically approximately 0.09to 0.10 mM.

The temperature of the metathesis reaction typically is in the range ofapproximately 25° C. to approximately 50° C.

The time required for the reaction typically is in the range ofapproximately 4 to approximately 24 hours, or until the conventionalanalytical techniques such as TLC or GC indicate that the reaction hasachieved completion.

In general, the time and temperature parameters of the reaction willvary somewhat depending on reaction concentration and stoichiometry. Theskilled artisan can readily adjust the reaction parameters as needed tooptimize reaction yields on a run-by-run basis.

In a typical procedure, (IV) is dissolved in dichloromethane. Themixture is degassed under vacuum, then purged with nitrogen. The mixtureis then warmed to reflux, Grubb's catalyst A

(CAS #1246047-72-3) in degassed dichloromethane is added. The mixture isallowed to stir at reflux for approximately 12 to approximately 24hours. Workup and purification under conventional procedures provides V.

Benefits of the approach to (V) via this ring closing reaction,particularly when a homogeneous catalyst is employed, include:

-   -   Smaller quantities of catalyst are needed because of typically        the high turnover numbers of homogeneous catalysts, increasing        efficiency and reducing the overall cost of the transformation;    -   The ability to run production-scale reactions in a minimal        amount of solvent, thus reducing waste management requirements        and environmental concerns;    -   The ability to run the reactions at room temperature and        atmospheric pressure, thus reducing the need to use specialized        pressurized production-scale apparatus, and simplifying work-up        procedures; and    -   An overall reduction in the number of synthetic steps needed to        make the compound stereoselectively.        Step (d)

Step (d) of the invention process is disclosed in U.S. Pat. No.6,476,235 (corresponding to U.S. Ser. No. 10/015,558, allowed as of Jul.22, 2002).

Step (e)

Step (e) of the invention process is disclosed in U.S. Pat. No.6,476,235 (corresponding to U.S. Ser. No. 10/015,558, allowed as of Jul.22, 2002) provides 1, which is a convenient precursor to atorvastatin.

EXAMPLES

The following examples are intended to illustrate various embodiments ofthe invention and are not intended to restrict the scope thereof.

Example 1 Preparation of5-(4-Fluoro-phenyl)-1-(3-hydroxy-hex-5-enyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide (III)

A flask was charged with 1.25 g (2.4 mmol, 1.14 equiv) of(S,S)-1,2-diamino-1,2-diphenylethane bis-toluenesulfonamide, followed by20 ml of CH₂Cl₂. The resulting mixture was cooled to 0° C. and 2.0 mL(2.33 mmol, 1.1 equiv) of BBr₃ was added dropwise. The reaction wasstirred at 0° C. for 10 minutes and then allowed to warm to ambienttemperature and stirred for an additional 40 minutes. The reactionmixture was concentrated in vacuo and taken up in 8 ml of CH₂Cl₂ andconcentrated in vacuo. Again, 20 ml of CH₂Cl₂ was added to the reactionmixture and the resulting solution was cooled to 0° C. To the cooledreaction mixture was added 0.75 ml (2.31 mmol, 1.1 equiv) of allyltributylstannane, after which the mixture was warmed to ambienttemperature and stirred for two hours. The reaction was cooled to −78°C. and 0.96 g (2.1 mmol, 1.0 equiv) of aldehyde (II) dissolved in 2.5 mlof CH₂Cl₂ was added dropwise. After three hours and an additional 0.5 gof aldehyde dissolved in 2.5 ml of CH₂Cl₂ was added dropwise and stirredovernight. The reaction was quenched by the addition of 10 ml of pH 6.2phosphate buffer. The organic layer was washed with 10 ml of saturatedaqueous sodium chloride and was then condensed. The resulting mixturewas dissolved in 10 ml of CH₂Cl₂ and diluted with 40 ml of heptane. Thechiral diamino auxiliary was recovered in 97% yield. The filtrate wasstirred with 20 ml of 33% aqueous KF to remove tin salts. The organiclayer was dried over MgSO₄ and condensed followed by dissolving in 50 mlof EtOAc filtering and again condensing. This was repeated with anadditional 12 ml of EtOAc and finally condensing to give 0.98 g (95%yield) of an oil. LC-MS API-ES negative ionization M 496.3 and M−1495.3; LC-MS API-ES positive ionization M 496.3 and M+1 497.3.

Example 2 Preparation of Acrylic acid1-{2-[2-(4-fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-ethyl}-but-3-enylester (IV)

To a flask was added 0.98 g (1.98 mmol, 1 equiv) of⁵-(4-Fluoro-phenyl)-1-(3-hydroxy-hex-5-enyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide (III) and 10 ml of CH₂Cl₂. The reaction was cooled to−5° C. and 0.33 ml (2.38 mmol, 1.2 equiv) of triethylamine and 0.048 g((0.396 mmol, 0.2 equiv) of 4-(dimethyl amino)pyridine were added. Tothe cooled reaction mixture was slowly added 0.19 ml (2.38 mmol, 1.2equiv) of acryloyl chloride dissolved in 10 ml of CH₂Cl₂. An additional0.33 mil of triethylamine and 0.048 g of 4-(dimethyl amino)pyridine wasadded to the reaction mixture, followed by 0.19 ml of acryloyl chloridedissolved in 3 ml of CH₂Cl₂. The reaction was quenched with 20 ml ofaqueous NaHCO₃. The organic layer was washed with 20 ml of aqueousNaHCO₃, followed by saturated aqueous NaCl, dried over MgSO₄, andconcentrated in vacuo to give 0.9 g (88% yield) (IV) as an orange solid.

HPLC Retention time 17.0 minutes wavelength at 254 nm.Acetonitrile:water w/0.1% formic acid 60:40 (0 to 5 min) 100:0 (15 to 22min) 60:40 (25 min), YMC ODS-AQ S5; 120 A; 4.6×250 mm; flow rate at 1ml/min and column temperature at 30° C.

Example 3 Preparation of5-(4-Fluoro-phenyl)-2-isopropyl-1-[2-(6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-4-phenyl-1H-pyrrole-3-carboxylicacid phenylamide (V)

To a flask was added 0.9 g (0.8 mmol, 1 equiv) of acrylate ester in 45ml of CH₂Cl₂. The mixture was degassed a single time under vacuumfollowed by nitrogen. The reaction was warmed to reflux. To the reactionmixture was added 0.035 g (0.04.mmol, 0.05 equiv) of Grubb's catalyst(CAS #1246047-72-3) in 5 ml of degassed solvent. The reaction wasallowed to stir at reflux for 19 hours. The mixture was condensed andsubjected to silica gel flash chromatography eluting with 10%EtOAc/heptane with a gradient increased to 40% EtOAc/heptane. Aftercondensing suitable fraction 0.3 g of a white solid (72% yield) wasisolated.

HPLC Retention time 13.3 minutes wavelength at 254 nm.Acetonitrile:water w/0.1% formic acid 60:40 (0 to 5 min) 100:0 (15 to 22min) 60:40 (25 min), YMC ODS-AQ S5; 120 A; 4.6×250 mm; flow rate at 1ml/min and column temperature at 30° C.

Chiral HPLC analysis hexane:isopropanol 90:10 Chirapak AD; 4.6×250 mm;flow rate at 1 ml/min and column temperature at 30° C.

(S) retention time 16.6 min

(R) retention time 19.1 min

Ratio of 97.22:2.78

94.4% enantiomeric excess.

All patents, and patent documents are incorporated by reference herein,as though individually incorporated by reference. The invention has beendescribed with reference to various specific and preferred embodimentsand techniques. However, it should be understood that many variationsand modifications may be made while remaining within the spirit andscope of the invention.

1. A process for preparing a compound of formula (I)

comprising: (a) contacting in a solvent optionally in the presence of a Lewis acid a compound of formula (II) with

wherein M is SiCl₃, SiMe₃, B(OH)₂, CuLi, MgBr, ZnBr, InBr, SnR₃ wherein R₃ is (C₁-C₆)alkyl, to give a compound of formula (III):

(b) conversion of the compound of formula (III) to an acryloyl ester of formula (IV) in the presence of base using wherein X is Cl, Br, I, or

and R is H, (C₁-C₆)alkyl, or phenyl, or an acryloyl activated ester equivalent;

(c) contacting in a solvent the acryloyl ester (IV) with a catalyst to afford 5,6 dihydro pyran-2-one V;

(d) converting the compound of formula (V) to a compound of formula (VI) via facial selective 1,4 addition of allyl or benzyl alcohol;

R′=benzyl, allyl and (e) removal of the allyl or benzyl moiety in the compound of formula (VI) via hydrogenolysis to give a compound of formula I.


2. The process of step (a) of claim 1, wherein

is allyl tri-n-butylstannane, allyl trimethylsilane, allyltrichlorosilane, allyl magnesium bromide, or allyl zinc bromide, optionally used in the presence of an amino alcohol or diamine or a Lewis Base.
 3. The process of step (a) of claim 1 carried out in the presence of a nonchiral or chiral Lewis acid, optionally generated in situ from boron tribromide and (S,S)-1,2-diamino-1,2-diphenylethane bis-toluenesulfonamide.
 4. The process of step (b) of claim 1 wherein the base is an amine base selected from the group consisting of triethyl amine, N,N dimethyl amino pyridine, DBU, and DBN optionally in the presence of a catalytic amount of DMAP and the polar nonprotic solvent is dichloromethane.
 5. The process of step (c) of claim 1, wherein the catalyst is

benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro (tricyclohexylphosphine)ruthenium.
 6. A process for the preparation of a compound of formula (I)

comprising: (a) contacting in a solvent optionally in the presence of a Lewis acid a compound of formula (II) with

wherein M is SiCl₃, SiMe₃, B(OH)₂, CuLi, MgBr, ZnBr, InBr, SnR₃ wherein R₃ is (C₁-C₆)alkyl, to give a compound of formula (III):

(b) conversion of the compound of formula (VII) with concomitant stereochemical inversion of the homoallylic alcohol center to an acryloyl ester of formula (IV) via Mitsunobu reaction in the presence of acrylic acid or an acrylic acid analogue

wherein R is H, (C₁-C₆)alkyl, or phenyl, in the presence of base;

(c) contacting in a solvent the acryloyl ester (IV) with a catalyst to afford 5,6 dihydro pyran-2-one V;

(d) converting the compound of formula (V) to a compound of formula (VI) via facial selective 1,4 addition of allyl or benzyl alcohol;

(e) removal of the allyl or benzyl moiety in the compound of formula (VI) via hydrogenolysis to give a compound of formula I.


7. A process for the preparation of a compound of formula (I)

comprising: (a) contacting in a solvent optionally in the presence of a Lewis acid a compound of formula (II) with

wherein M is SiCl₃, SiMe₃, B(OH)₂, CuLi, MgBr, ZnBr, InBr, SnR₃ wherein R₃ is (C₁-C₆)alkyl, to give a compound of formula (VIII):

(b) isolating the desired enatiomer (VIII) from the enantiomeric mixture;

(c) conversion of the compound of formula (III) to an acryloyl ester of formula (IV) in the presence of base using

wherein X is Cl, Br, I, or

and R is H, (C₁-C₆)alkyl, or phenyl, or an acryloyl activated ester equivalent;

(d) contacting in a solvent the acryloyl ester (IV) with a catalyst to afford 5,6 dihydro pyran-2-one V;

(e) converting the compound of formula (V) to a compound of formula (VI) via facial selective 1,4 addition of allyl or benzyl alcohol;

(f) removal of the allyl or benzyl moiety in the compound of formula (VI) via hydrogenolysis to give a compound of formula I.


8. A process for the preparation of a compound of formula III

comprising: (a) contacting a compound of formula (II) with an allenylboronic ester to give a compound of formula (XI):

(b) hydrogenation of the compound of formula (XI) to provide III


9. A process for the preparation of a compound of formula VII

comprising: (a) contacting contacting (II) with an allenylboronic ester to give a compound of formula (XII):

(b) hydrogenation of the compound of formula (XII) to provide VII


10. A process for the preparation of a compound of formula VIII

comprising: (a) contacting (II) with allenylboronic acid or an allenylboronic ester to give a compound of formula (XIII):

(b) hydrogenation of the compound of formula (XII) to provide VII


11. Compounds of the following formulas:

wherein R is H, (C₁-C₆)alkyl, or phenyl. 